2-methyl-3-hydroxy-5-cyanopyridine-1-oxide and corresponding 1-alkoxy pryidinium alkyl sulfate salt



United States Patent 3 313 820 2 METHYL 3 HYDliOX Y 5 CYANOPYRIDINE- l-OXIDE AND CORRESPONDING l-ALKOXY PRYIDINIUM ALKYL SULFATE SALT Patented Apr. 11, 1967 The steps in the above formula will be given in further detail.

Z-methyl-3hydroxy-Scyanopyridine, when allowed to react with hydrogen peroxide in glacial acetic acid by Takeo Naito, Ichikawa-shi, Tom Yoshikawa, Urawa-shi, 5 83??? i g g ig gg g ggc ig ggo g gg and Fumiyoshi Ishikawa, Ichikawa-shi, Japan, assignors th h d p 5 y 1 734507 to Daiichi Seiyaku Company, Limited, Chuo-ku, Tokyo, 2 Y YOXY' E OX1 e m 0 Japan yield. This substance s a new compound, colorless crys- No Drawing. Filed Mar. 12, 1965, Ser. No. 439,474 tals wlth a decomposmon p t of Prop- Claims riority, appligcatliggilgpan, Mar. 12, 1964, 10 erties of this compound are indicated below:

3 2 Claims. (Cl. 260294.8) TABLE OF PROPERTIES I This invention relates to a process for preparing 2- g fi 5 g f methyl-3-hydroxy-4,5-dicyanopyridine and further recoprt a 9 C (d lates to the novel chemical compounds for use in the pom ecomp') S 1 5 {P- preparation of the same. so u 1 lty n o 6 g 2-methyl-3-hydroxy-4,S-dicyanopyridine is an interi g g mediate for vitamin B and was produced by condensae m ct er an tion of ethoxymethylene succinonitrile with an alanine Zena ester (Makino et al.: Bulletin of the Chemical Society Z-methyl-3-hydroxy-S-cyanopyridine-l-oxide is alkylof Japan, 19, l, 1944) or by condensation of 4-rnethyl-5- ated with di-lower alkyl sulfates by heating at a temperaethoxyoxazole with fumaronitrile (E. E. Harris et al.: ture of from 70 to 150 C., preferably 80 to 130 C.,

Journal of Organic Chemistry, 27, 2705, 1962). most preferably 100 to 110 C., to obtain l-lower It is an object of the present invention to provide an alkoxy-2-methyl-3hydroxy 5 cyanopyridinium lower economical and convenient method for synthesizing 2- alkyl sulfate. The ethyl sulfate having decomposition methyl-3-hyd'roxy-4,S-dicyanopyridine. point of 129130 C. is obtained in 82 to 85% yield. It is another object of the present invention to provide The di-lower alkyl sulfates includes those where the alkyl 21 method for preparing the above compound in a simple groups have 1 to 4 carbon atoms, preferably methyl and manner and with high yield. According to the present ethyl. The alkoxy likewise are those having 1 to 4 carinvention, 2-methyl-3hydroxy-S-cyanopyridine is oxibon atoms. The resultant lower alkyl sulfates are novel dized in glacial acetic acid with hydrogen peroxide to compounds, properties of which are given below.

TABLE OF PROPERTIES II R 0R Crystals niiiililfi) Solubility point, 0. Form I Color Soluble in H 0, OH 0H, 0 H OH 851 ;233:313: 1512359525331: di i -1555f: "ii;i6'} g g gg g i115 produce 2 methyl 3 hydroxy-S-cyanopyridine-l-oxide The l-lower alkoxy 2 methyl-3hydroxy-S-cyanopyriwhich is then treated with a di-lower alkyl sulfate for dinum lower alkyl sulfate thus obtained is then allowed conversion into l-lower alkoxy-2-methyl-3hydroxy-S- to react with an alkali cyanide in an aqueous solution at cyanopyn'dinium lower alkyl sulfate. The sulfate is fura lower temperature to produce 2-methyl-3-hydroxy-4,5-

ther treated with an alkali metal cyanide to produce the dicyanopyridine having a melting point of 189-190 C.,

desired Z-methyl-3-hydroxy-4,5dicyanopyridine. which is obtained in 78-80% yield. The alkali cyanides The process of the present invention may be illustrated include sodium cyanide and potassium cyanide. The

as follows: lower temperature is from 0 to 20 C., preferably from 0 to 10 C., most preferably from 5 to 7 C. HO ON H202 H0 ON R2804 In the present process, we have found that the cyano group is introduced specifically in the C.,-position of the H30 \N H3O \N pyridine nucleus. Conventionally, the cyano group was J, introduced in the C or C -position. References have 0 been made to this fact, for example, in Okamoto and 2-methyl-3-hydroxy- 2methyl-3- hydr0Xy- Tani: Chemical and Pharmaceutical bulletin, vol. 7, p. Scyanopyndme fi-wanopyndme-lexlde 130 1959 and w. E. Feely et al.: Journal of the Ameri- HO GN can Chemical Society, vol. 81, p. 4004 (1959).

I Rsor 2 3 In the process of the present invention, isolation of the H30 H0 ON l-lower alkoxy-Z-methyl-Bhydroxy 5 cyanopyridinium N J lower alkyl sulfate is not required, and it is also possible I R H30 \N to subject directly the reaction product obtained by alkyll-lower alkoxy-2-methyl-3- 2-methyl-3-hydroxyating znmethyl'3. hydr9xysCyanopyridine:lhoxide to hydroxy-5'cyanopyridinium 4,5-dicyanopyridine subsequent reaction with an aqueous solution of an alkali alkyl Sulfate metal cyanide. Thus, the operation is simplified and yet a high yield is ensured. wherein -R represents a lower alkyl group and M repre- The following examples illustrate specific methods of sents an alkali metal.

carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1.Into 90 of hot glacial acetic acid, 4.0 g. of 2-rnethyl-3-hydroxy-5-cyanopyridine was dissolved, and then, with the addition of 6 ml. of 30% hydrogen peroxide, heated in a boiling water bath for one hour. Again, with the addition of 6 ml. of 30% hydrogen peroxide, the mixture was heated for one hour. The above procedure was repeated three times altogether. By further heating for 4 hours, the reaction was brought to an end. After half the total amount of acetic acid was distilled off, the solution was allowed to cool, and the precipitated crystals were filtered. The yield was 2.9 g. On concentration, the filtrate gave further 0.4 g. of crystals. Altogether, 3.3 g. (73.4%) of 2-methyl-3-hydroxy- S-cyanopyrid-ine-l-oxide, M.P. 278280 C. (decomp.), was obtained.

Analysis for C H N O Calculated (percent): C, 56.00; H, 4.03; N, 18.66. Found (percent): C, 55.68; H, 4.08; N, 18.10. Ultraviolet absorption: k 241 m 328 my. (in ethanol).

A thorough mixture of 0.7 g. of 2-methyl-3-hydroxy- S-cyanopyridine-l-oxide obtained above and 0.7 g. of diethyl sulfate was heated in an oil bath at 100-110 C. The reaction mixture was gradually colored and melted together. After two hours, the reaction was brought to an end, and the resultant solidified on cooling. The said solid matter was washed with a small amount of acetone to give 0.85 g. of crystals. From the filtrate, 0.31 g. of crystals was further obtained. Altogether, 1'ethoxy-2- methyl-3-hyd roxy--cyanopyridinium ethyl sulfate, M.P. l29l30 C. (decomp.), was obtained in 82.1% yield.

Analysis for C H N O S. Calculated (percent): C, 43.41; H, 5.31; N, 9.22. Found (percent): C, 43.75; H, 5.56; N, 9.06.

Into 5 ml. of water, 1.5 g. of 1-ethoxy-2-methyl-3-hyd-roxy-S-cyanopyrirdinium ethyl sulfate obtained above was dissolved and cooled to 5 C. This solution was introduced dropwise with stirring into a solution of 0.54 g. of sodium cyanide in 8 m1. of water at 57 C. over a period of 25 minutes. After the completion of the drip-ping, the temperature was gradually raised to room temperature, and then the mixture was allowed to stand for 1.5 hours. The reaction solution was acidified with hydrochloric acid (to pH 2), and precipitated crystals were collected by filtration, whereupon 0.75 g. of 2- methyl-3-hydroxy-4,S-dicyanopyridine, M.P. 189190 C., was obtained in 85% yield in terms of the monohydrate. On drying, the product turns to a yellowish crystalline powder.

Analysis for C H N O. Calculated (percent): C,

4 60.37; H, 3.15; N, 26.40. Found (percent): C, 59.73; H, 3.36; N, 26.81.

The product, when melted in mixture with an authentic sample synthesized according to the Harris process, showed no drop in the melting point. Also, it entirely agreed with the latter in ultraviolet and infrared absorption values.

Example 2.A mixture of 0.6 g. of 2-methy1-3-hydroxy-S-cyanopyridine-l-oxide prepared according to EX- ample 1 and 0.55 g. of dimethyl sulfate was heated at 110 C. for two hours. The mixture was gradually colored and melted to give reddish oily substance which would not solidify on cooling. This oily substance was dissolved in 5 ml. of water, and introduced, while being cooled with ice water, dropwise into a solution of 0.65 g. of potassium cyanide in 8 ml. of water at 5-7 C. The temperature of the reaction solution was gradually raised to room temperature, and the solution was allowed to stand for 1.5 hours. The reaction solution was acidified with hydrochloric acid, and the precipitated crystals was filtered and collected to give 0.55 g. of 2-methyl-3-hydroxy-4,S-dicyanopyridine in a 78% yield in terms of the monohydrate. On drying, the product turned to a yellowish crystalline powder, M.P. 189- 190 C.

What is claimed is:

1. 2-rnethyl-3-hydroxy-5cyanopyridine-1-oxide having the formula:

2. l-lower al koxy-2-methyl-3-hydroxy-5-cyanopyridinium lower alkyl sulfate having the formula:

ON I RS04- H O I H3O I OR References Cited by the Examiner UNITED STATES PATENTS 2/1961 Feely 260294.9 7/1961 Feely 260294.9 

1. 2-METHYL-3-HYDROXY-5-CYANOPYRIDINE-1-OXIDE HAVING THE FORMULA: 